Abstract
Microtubule-associated protein tau is hyperphosphorylated and aggregated in affected neurons in Alzheimer disease (AD) brains. The tau pathology starts from the entorhinal cortex (EC), spreads to the hippocampus and frontal and temporal cortices, and finally to all isocortex areas, but the cerebellum is spared from tau lesions. The molecular basis of differential vulnerability of different brain regions to tau pathology is not understood. In the present study, we analyzed brain regional expressions of tau and tau pathology-related proteins. We found that tau was hyperphosphorylated at multiple sites in the frontal cortex (FC), but not in the cerebellum, from AD brain. The level of tau expression in the cerebellum was about 1/4 of that seen in the frontal and temporal cortices in human brain. In the rat brain, the expression level of tau with three microtubule-binding repeats (3R-tau) was comparable in the hippocampus, EC, FC, parietal-temporal cortex (PTC), occipital-temporal cortex (OTC), striatum, thalamus, olfactory bulb (OB) and cerebellum. However, the expression level of 4R-tau was the highest in the EC and the lowest in the cerebellum. Tau phosphatases, kinases, microtubule-related proteins and other tau pathology-related proteins were also expressed in a region-specific manner in the rat brain. These results suggest that higher levels of tau and tau kinases in the EC and low levels of these proteins in the cerebellum may accounts for the vulnerability and resistance of these representative brain regions to the development of tau pathology, respectively. The present study provides the regional expression profiles of tau and tau pathology-related proteins in the brain, which may help understand the brain regional vulnerability to tau pathology in neurodegenerative tauopathies.
Highlights
Neurofibrillary pathology made up of hyperphosphorylated tau is the common feature of a family of neurodegenerative disorders collectively termed tauopathies, which include Alzheimer’s disease (AD), argyrophilic grain disease (AGD), Pick’s disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and several others (Tolnay and Probst, 1999; Lee et al, 2001)
Tau Is Hyperphosphorylated in the Frontal Cortex but Not in the Cerebellum from Alzheimer disease (AD) Brains In AD brain, neurofibrillary tau pathology is observed in multiple brain regions including the hippocampus, entorhinal cortex (EC), temporal and frontal cortices and other areas (Braak and Braak, 1991); the cerebellum is spared from tau pathology (Larner, 1997)
To identify whether tau is hyperphosphorylated in AD cerebellum, we determined the level of tau phosphorylation in the cerebellum vs. the frontal cortex (FC) of frozen post-mortem AD and non-affected control brains using immuno-dot blots, which were developed with antibodies recognizing tau phosphorylated at varying sites
Summary
Neurofibrillary pathology made up of hyperphosphorylated tau is the common feature of a family of neurodegenerative disorders collectively termed tauopathies, which include Alzheimer’s disease (AD), argyrophilic grain disease (AGD), Pick’s disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and several others (Tolnay and Probst, 1999; Lee et al, 2001). In the brain with AD or AGD, tau pathology is initiated in the entorhinal cortex (EC) and follows a stereotypical pattern to progressively propagate to the limbic system and eventually to widespread isocortex regions (Braak and Braak, 1991; Saito et al, 2004; Braak and Del Tredici, 2011). AD cases some brain areas such as the cerebellum are relatively spared from tau pathology (Larner, 1997). It seems that some regions of the brain are more vulnerable whereas the others are more resistant to the development of tau lesions (Kaufman et al, 2016). S. et al, 2007; Liang et al, 2008), and that phylogenetic diversity of tau isoforms expressed in different mammalian species has been proposed to link to particular vulnerability of the human brain to tau pathology (Janke et al, 1999), the exact nature of molecular basis underlying the differential vulnerability to tau pathology is not understood
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